Open AccessTime‐to‐Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine‐Citrulline‐Monomethylauristatin E Antibody–Drug Conjugates
Author(s) -
Kågedal Matts,
Samineni Divya,
Gillespie William R.,
Lu Dan,
Fine Bernard M.,
Girish Sandhya,
Li Chunze,
Jin Jin Y.
Publication year - 2019
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12442
Subject(s) - medicine , discontinuation , peripheral neuropathy , adverse effect , regimen , citrulline , dosing , incidence (geometry) , drug , toxicity , pharmacology , gastroenterology , oncology , arginine , endocrinology , diabetes mellitus , chemistry , biochemistry , physics , amino acid , optics
Peripheral neuropathy (PN) is a common long‐term debilitating toxicity of antimicrotubule agents. PN was the most frequent adverse event resulting in dose modifications and/or discontinuation of treatment for valine‐citrulline‐monomethylauristatin E antibody–drug conjugates (ADCs) developed at Genentech. A pooled time‐to‐event analysis across eight ADCs (~700 patients) was performed to evaluate the relationship between the ADC exposure and the risk for developing a clinically significant (grade ≥ 2) PN. In addition, the impact of demographic and pathophysiological risk factors on the risk for PN was explored. The time‐to‐event analysis suggested that the development of PN risk increased with ADC exposure, treatment duration, body weight, and previously reported PN. This model can be used to inform clinical strategies such as adaptations to dosing regimen and/or treatment duration as well as inform clinical eligibility to reduce the incidence of grade ≥ 2 PN.